Compositions containing an antifungal and a phospholipid

ABSTRACT

The invention relates to compositions such as body and hair cleansing products, in particular shampoos, comprising one or more antifungals inhibiting fungal ergosterol biosynthesis as a first active ingredient, a synthetic, amphotheric phospholipid acting both as a second active ingredient and as a surface active agent, and art-known body or hair cleansing product ingredients as a carrier.

CROSS REFERENCE TO RELATED APPLICATION

This application is a National Stage application under 35 U.S.C 371 ofPCT/EP98/02143 filed Apr. 7, 1998, which claims priority from EP97.201.101.9, filed Apr. 14, 1997.

The invention relates to compositions such as body and hair cleansingproducts, in particular shampoos, comprising one or more antifungalsinhibiting fungal ergosterol biosynthesis as a first active ingredient,a synthetic, amphotheric phospholipid acting both as a second activeingredient and as a surface active agent, and art-known body or haircleansing product ingredients as a carrier.

BACKGROUND OF THE INVENTION

Known medicated shampoos are, for example, the ketoconazole shampooswhich are marketed in a 2% formulation and which show a beneficialeffect in dandruff and seborrheic dermatitis after topical application.Ketoconazole was disclosed by Rosenberg et al. in U.S. Pat. No.4,569,935 to be useful in the topical treatment of psoriasis andseborrheic dermatitis. Ketoconazole shampoos that exhibit bettercosmetic attributes such as lathering and conditioning, and areacceptably stable to degradation so that they can be formulated tocontain less than 2% active ingredient are disclosed in U.S. Pat. No.5,456,851. Elubiol shampoos having a skin grease regulating action areknown from WO-93/18743. Some anti-dandruff formulations contain coaltar, selenium sulfide or a pyrithione salt, e.g. zinc or sodiumpyrithione as an active agent. WO-96/29045 generically disclosescombinations of such a cytotoxic agent and an antifungal agent for thetreatment of seborrheic dermatitis of the scalp; specifically disclosedis the combined use of an unidentified composition comprising 1.8% coaltar and an unidentified solution comprising 2% ketoconazole. WO-96/29983discloses mild aqueous detergent compositions comprising from about 4 toabout 12% by weight of an anionic surfactant, an amphoteric surfactantat a level of at least about 0.75 parts by weight per part by weight ofsaid anionic surfactant, and one or more of 11 listed therapeuticagents.

U.S. Pat. No. 4,209,449 (EP-0,013,713) discloses synthetic, amphothericphospholipids which exhibit outstanding foaming, viscosity-building,wetting, cleansing, detergency, anti-static and emulsifying properties.A number of the synthetic, amphotheric phospholipids described thereinare commercially available from Mona Industries, Inc., Paterson, N.J.,USA under the name Phospholipid PTC (cocamidopropyl phosphatidylPG-dimonium chloride), Phospholipid EFA (linoleamidopropyl phosphatidylPG-dimonium chloride), Phospholipid PTS (stearamidopropyl phosphatidylPG-dimonium chloride).

Prior art shampoos comprising anti-dandruff agents are designed in sucha way that an optimum balance is achieved between efficacy andtolerability; the concentration of the active ingredient in themedicated shampoos is such that as many users as possible areeffectively treated and as few as possible suffer adverse effects.Nonetheless, there remain substantial numbers of patients who do notbenefit from using prior art shampoos, either because they do notrespond to the treatment, or worse, because they do not tolerate thetreatment with a particular medicated shampoo.

The number of patients not responding to particular medicated shampoocan be quite high (ketoconazole up to 30% ; selenium sulfide up to 40%).Consequently, there is a hard felt need for new shampoos which provideeffective anti-dandruff treatment for a larger proportion of number ofpatients using such a new shampoo; i.e. a new shampoo for which thereare fewer non-respondents than with prior art shampoos.

On the other hand, patients suffering from dandruff or seborrheicdermatitis, as well as the authorities approving medicated shampoos,apply increasingly stricter criteria which such shampoos should meet.Amongst these criteria the most important are: absence of furtheraggravation of the condition due to the treatment, lowest possibleincidence of side effects, further increase in the absence of symptomssuch as irritation, pruritus and scaling (both adherent and loosescaling); improved cosmetic acceptability, in particular, good cleansingproperties, absence of odour or stench, absence of staining or soilingof the clothes, and overall conditioning (wet and dry combingproperties). Dandruff or seborrheic dermatitis are often accompanied byhigh or excessive oil or sebum production, and compositions having abeneficial effect thereon would clearly constitute a further advance inthe treatment of dandruff.

Thus far, in order to achieve the above desiderata, most efforts haveinvolved reformulating the shampoo base. There is, however, still a needfor increasing the tolerability/acceptability of medicated shampoos,i.e. new shampoos are desired that are tolerated better by largerproportions of patients using such new shampoos.

DESCRIPTION OF THE INVENTION

The present invention relates to compositions such as body and haircleansing products, in particular shampoos, comprising, consistingessentially of or consisting of one or more antifungals inhibitingfungal ergosterol biosynthesis as a first active ingredient, asynthetic, amphotheric phospholipid as a second active ingredient, andart-known body and hair cleansing product ingredients as a carrier. Inthe following description, the invention is illustrated using shampoosas examples, but it will be evident to a person skilled in the art thatthe combinations according to the present invention can be utilized justas well in other body and hair cleansing products.

The combination of two differently acting anti-dandruff agents has twodistinct advantages over the prior art shampoos which contain either ofthe active ingredients alone. First, an increased proportion of patientssuffering from dandruff or seborrheic dermatitis respond to the shampoosaccording to the present invention. Secondly, some combinations actsynergistically and as a consequence thereof, the concentration of oneor both of the different types of agent can be lowered, thus increasingthe tolerability. Each class of ingredients will now be discussed inturn.

Many of the ingredients discussed hereinafter are commercially availablein formulations (e.g. aqueous solutions), not as pure compounds. Theamount of ingredient which can be used in preparing formulationsaccording to the present invention are usually expressed as % (w/w) andrefer to the amount of the commercially available product to be used,not the amount of pure product.

The antifungal inhibiting fungal ergosterol biosynthesis is preferablyan azole, an allylamine, or a mixture thereof. Preferred azoles areselected from the group comprising ketoconazole, econazole, elubiol,miconazole, itraconazole, fluconazole and mixtures thereof. Preferredallylamines are selected from the group comprising terbinafine,naftifine and mixtures thereof. The azole compounds ketoconazole,econazole and elubiol are most preferred because they harm the normalflora of the skin, in particular of the scalp, the least. Ketoconazoleand elubiol are especially preferred as they produce a mutualsynergistic effect on dermatophyte fungi when in used in combinationwith a phospholipid (vide infra). Effective amounts of the antifungalsin compositions according to the present invention are in the range offrom about 0.1% to about 2% (w/w), and preferably from about 0.5% toabout 1% (w/w). As will be explained further, at the lower end of thisrange, special precautions may have to be taken in order to ensure thatthe shampoo does not lose its efficacy due to degradation of theantifungal compound upon storage. Concentrations higher than thoseindicated do not improve the treatment of the conditions any further,and are on the whole more detrimental than beneficial.

The second active ingredient is a synthetic, amphotheric phospholipidhaving the formula

wherein R represents a straight, saturated, mono-unsaturated orpoly-unsaturated C7-19 alkyl group; x represents 1, 2 or 3 and x+y=3;and mixtures thereof. The radical R—(C═O)— thus represents the acylresidue of a straight, saturated, mono-unsaturated or poly-unsaturatedC8-20 carboxylic acid; examples of such acids are octanoic (caprylic),nonanoic, decanoic (capric), undecanoic, 10-undecenoic, dodecanoic(lauric), tridecanoic, tetradecanoic (myristic), pentadecanoic,hexadecanoic (palmitic), palmitoleic, heptadecanoic, octadecanoic(stearic), 9-octadecenoic (oleic), 9,12-octa-decadienoic (linoleic),9,12,15-octadecatrienoic (linolenic), nonadecanoic, eicosanoic(arachidic) and 5,8,11,14-eicosatetraenoic (arachidonic) acid. Thephospholipids may be present in an amount ranging from about 0.04% toabout 10% (w/w), and preferably from about 0.25% to about 2% (w/w). Oneskilled in the art will readily recognize that the nature of theparticular phospholipid form has an effect on the amount when expressedas % (w/w). Preferred phospholipids are those wherein R—(C═O)—represents the acyl residue of stearic, linoleic or coconut fatty acid(which is a mixture of lauric, myristic, palmitic and stearic acids).The phospholipids and their preparation are known from U.S. Pat. No.4,209,449. Some are commercially available from the assignee of saidpatent, Mona Industries, Inc, Paterson, N.J., USA: e.g. Phospholipid PTC(cocamidopropyl phosphatidyl PG-dimonium chloride), Phospholipid EFA(linoleamidopropyl phosphatidyl PG-dimonium chloride), Phospholipid SV(palmitamidopropyl phosphatidyl PG-dimonium chloride), and PhospholipidPTS (stearamidopropyl phosphatidyl PG-dimonium chloride).

Phospholipid PTC is the most preferred second active ingredient and isan aqueous formulation having a solid contents of 47%, appearing as aclear yellow liquid and giving a pH of about 7 when diluted to 10% in50/50 2-propanol/water.

Preferably, the first and the second active ingredients are present inquantities producing a mutual synergistic effect on the inhibition ofthe growth of dermatophyte fungi, in particular the species associatedwith dandruff and seborrheic dermatitis, i.e. Malassezia furfur(Pityrosporum ovale), but also other fungi such as Epidermophyton,Microsporum, Trichophyton species associated with, for example,dermatophytosis. pityriasis versicolor and the like. The ratio of thequantities of the first and the second active ingredient will depend onthe nature of said active ingredients and on the target species.Particularly, it is contemplated that the weight:weight ratio betweenthe first and the second active ingredient (antifungal:pyrithione) mayrange from about 5:1 to about 1:150, in particular from about 2:1 toabout 1:25. For example, and as already mentioned, ketoconazole andelubiol when in used in combination with a phospholipid, in particularwhen used in similar quantities such as in a weight ratio ranging fromabout 2:1 to about 1:25, in particular in a weight range of about 1:20,produce a mutual synergistic effect on fungi, in particular onMalassezia furfur.

The shampoos according to the present invention can conveniently beformulated using art-known shampoo bases; the art-known shampooingredients comprise one or more of a surfactant, a foaming agent, athickener, a preservative, an anti-oxidant, and acid or base or buffersufficient to give the shampoo a pH in the range of from about 4 toabout 10. A single ingredient can have two or more functions, e.g.surfactant and foaming agent, or anti-oxidant and buffer.

Suitable surfactants for use in the shampoos according to the presentinvention may be selected from the group comprising sodium C14-16 olefinsulfonates, sodium lauryl sulfate, TEA lauryl sulfate, sodium laurethsulfate, cocamidopropylamine oxide, lauryl amine oxide, lauramido DEA,cocamidopropyl betaine, lauryl dimethyl betaine, cocodimethylsulfo-propyl betaine, sodium cocoyl sarcosinate, disodium oleamido MIPAsulfosuccinate, disodium cocamido MIPA sulfosuccinate, disodium laurethsulfosuccinate, cocoamphocarboxy-glycinate, disodium oleamido MEAsulfosuccinate, amine glycinates, amine propionates and amine sultaines,and mixtures thereof. Preferably, a mixture of two or more differentsurfactants, in particular sodium laureth sulfate and sodium cocoylsarcosinate; or sodium laureth sulfate and disodium laurethsulfosuccinate; or sodium lauryl sulfate, sodium laureth sulfate, TEAlauryl sulfate and cocamidopropyl betaine, may be used in the presentshampoos. In the shampoos according to the present invention, the totalamount of surfactants may range from about 36% to about 55% (w/w).Preferably, the weight of amphoteric surfactants is less than 15% byweight of the total amount of surfactants.

In the above definitions, and hereinafter, the term ‘MEA’ signifies amono-ethanolamide of formula RCO—NH—CH₂CH₂—OH, the term ‘DEA’ signifiesdi-ethanol amide of formula RCO—N(CH₂CH₂—OH)₂, ‘TEA’ signifiestriethanolammonium; the term ‘MIPA’ signifies a mono-isopropanol amideof formula RCO—NH—CH₂—CHOH—CH₃; wherein each RCO-group is a fatty acidresidue, such as a C13-19alkylcarbonyl or C13-19alkenylcarbonyl group.

Suitable foaming agents (foam boosters and stabilizers) for use in theshampoos according to the present invention may be selected from thegroup of fatty acid mono- and dialkanol-amides comprising cocamide MEA,cocamide DEA, oleamide MEA, oleamide DEA and mixtures thereof. Thefoaming agent may be present in a range from about 1 to about 10% (w/w),preferably from about 2 to about 6% (w/w), in particular about 4 toabout 5% (w/w). These ingredients typically also have a thickeningeffect on the formulation.

Suitable preservatives for use in the present shampoos aredermatologically acceptable preservatives, e.g. tetrasodium or disodiumEDTA, methylparaben, propylparaben, butylparaben, ethylparaben,imidazolidinyl urea, phenoxyethanol, quaternium 15, citric acid,preferably in combinations with one another. Tetrasodium and disodiumEDTA, and citric acid also function as chelating agents.

As disclosed in U.S. Pat. No. 5,456,851, when the concentration ofketoconazole, or for that matter that of any other antifungal, is at thelower end of the ranges mentioned hereinabove, the addition of acarefully controlled amount of an antioxidant selected from the groupconsisting of butylated hydroxytoluene (“BHT”), butylatedhydroxy-anisole (“BHA”), ascorbic acid and N-acetyl-cysteine effectivelystabilizes the ketoconazole or other azole present in the shampooagainst degradation during accelerated aging for 13 weeks at 50° C.,which is considered to be predictive of performance during storage atambient temperatures for two years. Effective stability is considered tobe a loss of active ingredient during storage of not more than about 10percent. The proportion of BHT or BHA that has been found to be mosteffective is within the range of from about 0.01% to about 1% (w/w).Proportions greater than this amount do not stabilize ketoconazole aseffectively for the 13-week accelerated aging period, although if oneextends the accelerated aging period longer than 13 weeks, greaterproportions of BHT or BHA tend to be more effective, since the BHT orBHA itself is also subject to degradation. However, it is wellrecognized by government regulatory agencies and in the pharmaceuticaland cosmetic industries that stability testing for 13 weeks at 50° C. isquite sufficient to predict product stability during normal shelf lifestorage for two (2) years at room temperature. It is also equallyimportant that, for safety reasons (that is, to minimize the potentialfor skin sensitization), it is desired to use as small an amount aspossible of BHT or BHA.

Since shampoo users expect a shampoo to be slightly viscous, one or morethickeners are often included in the formulation which give it aviscosity in the range of 4,000 to 9,000 mPa.s at room temperature. Asuitable thickener is a carbomer or polycarboxylic acid, such asCarbopol™ 1342 or Carbopol™ 1382, which is thickened by the addition ofsodium hydroxide or sodium chloride at the end of the preparation. Othersuitable thickeners are the foaming agents mentioned hereinabove,preferably cocamide MEA.

The shampoo may further comprise one or more pearlizing agents selectedfrom the group consisting of ethylene glycol distearate, ethylene glycolmonostearate and mixtures thereof, at a concentration of 0.0% to 2% ;one or more plant extracts, e.g. from aloe, arnica, birch, bladderwrack, gentian, ginseng, hamamelis (witch hazel), hawthorn, kina, lemon,nasturtium, rosemary, tea tree and the like, at a concentration of from0.0% to 5% ; vitamins such as, for example, vitamin E (tocopherol) andderivatives, e.g. tocopheryl acetate, panthenol, and the like, at aconcentration of 0.0% to 3%; antiinflammatory products of synthetic ornatural origin, e.g. bisabolol, at a concentration of 0% to 5%;fragrances at a concentration of 0% to 2%; and one or more colorants.

The shampoo may further comprise from 0.0% to 10% of a conditioner suchas polyquaternium-7, polyquaternium-10 or a similar cationic quaternarypolymer, e.g. a quaternary silicone polymer. Also suitable are othersilicone compounds such as polyalkyl siloxanes, polyalkyl arylsiloxanes,polyether siloxane copolymers and mixtures thereof. Polyalkyl siloxanesuseful herein include, for example, polydimethylsiloxanes (PDMS).Polyalkylaryl siloxanes that may be used includepolymethylphenylsiloxanes. Polyether siloxane copolymers that may beused include polypropyleneoxide modified polydimethylsiloxanes. Ethyleneoxide or mixtures of ethylene oxide and propylene oxide may also beused. The water insoluble ones are preferred. Gums of the abovedescribed siloxane polymers are most desirable for use herein. Thesesiloxane polymer gums are rigid as opposed to a liquid or fluid, withhigh mass molecular weights of from about 200,000 to about 1,000,000 andviscosities from about 100,000 mPa.s to about 150,000,000 mPa.s at 25°C. Polydimethyl siloxane gums are preferred. These gums have a viscosityof from about 100,000 mPa.s to about 150,000,000 mPa.s at 25° C. Thegums selected for use herein have a viscosity such that when blendedwith a PDMS fluid the viscosity of the blend of gum and fluid fallswithin this range. Such PDMS fluids are used at levels from about 50% toabout 60% of the total weight of said gum-fluid blend. Most preferredfor the present invention is a blend containing from about 40% to about60% PDMS fluid and from about 60% to about 40% PDMS gum. The preferredPDMS fluid is dimethicone fluid which has a viscosity of about 350 mPa.sat 25° C.

The pH of the shampoos according to the present invention areconveniently established using dermatologically acceptable acids, basesand buffers. The pH can range from about 4 to about 10, but preferablyis in the range of about 6.5 to about 8, in particular from about 6.9 toabout 7.4.

Some of the first active ingredients when at approximately neutral pH(pH 6 to 8), have limited solubility. In order to keep these agentshomogeneously distributed throughout the shampoo, a suspending agentsuch as, for example, Avicel RC-591™ (a mixture of sodium CMC andmicrocrystalline cellulose) may be added. Several of the shampoo baseingredients, however, have considerable suspending properties of theirown, and therefore the inclusion of particular suspending agents in thepresent shampoos is entirely optional.

The components of the shampoo are employed in conventional amounts, forexample:

-   -   (a) 36% to 55% surfactants,    -   (b) 2% to 6% foaming agent,    -   (c) 0.1% to 2% antifungal,    -   (d) 0.05 to 2% phospholipid    -   (e) 0.2% to 1.3% thickener,    -   (f) 0.01% to 1% BHT or BHA;    -   (g) preservatives sufficient to retard degradation of the final        composition in order to give adequate shelf life,    -   (h) acid, base or buffer to yield a pH in the desired range, and    -   (i) water qs ad 100% (that is, sufficient water to make 100%).

EXAMPLES

In the following, a general process for preparing shampoos according tothe present invention is presented. Suitable amounts for each of theingredients can be derived from the preceding description and from theexemplary formulations shown in the tables hereinafter.

A vessel was charged with a 1.64% stock solution of Carbopol 1342(prepared using a Quadro disperser which functions by keeping thepowdered polymer evenly divided and pulling the powder by a vacuum intoa stream of water) and deionized water, and heated to about 70° C. Bothsurfactants, i.e. sodium laureth sulfate and sodium cocoyl sarcosinate,were added, followed by the foaming agent, cocamide MEA, and apearlizing agent (ethylene glycol distearate) and mixed until completedissolution. Then the BHT was added and the mixture was stirred untilcomplete dissolution thereof. The solution was allowed to cool slightly,whereupon the antifungal ingredient was added while stirring well. (Theantifungal is added while the pH is slightly acidic, to facilitatedissolution.) Next, the phospholipid was dispersed into the mixture andstirred until homogenously dispersed. The mixture was allowed to cool toabout 40° C., at which temperature there were added the conditioner(polyquaternium-7), the preservatives quaternium-15 and tetrasodiumEDTA, the colorants and fragrances, and the NaCl for thickening thesolution. The pH of the solution was adjusted to 6.9-7.4 with a 25% aq.solution of NaOH and deionized water was added to the final volume.Similar shampoo formulations can prepared using analogous processeswhich will be apparent to the person skilled in the art.

Using the general procedures described above, the following shampooformulations according to the present invention can be made; allquantities hereinafter are parts by weight.

The formulations according to the present invention are useful in thetreatment of disorders such as dandruff, seborrheic dermatitis, thecontrol of psoriasis, the reduction of oil or sebum production of thescalp, and the like disorders and discomforts. The formulations are tobe applied topically to the affected body parts at regular intervals, inparticular from at least once weekly to about once daily. Preferablythey are employed more often in the beginning of the treatment, e.g.from 4 to 7 times a week, and less frequently in a later stage when thedesired effect has been obtained and relapse is to be prevented (e.g.once or twice a week).

Example 1 Shampoo Formulations for Normal Hair (with Conditioner)

Ingredients (a) (b) sodium laureth sulfate 30 30 sodium cocoylsarcosinate 10 10 cocamide MEA 4 4 ketoconazole USP 0.5 1 PhospholipidPTC 0.5 1 glycol distearate 1.25 1.25 polyquaternium-7 1 1 Carbopol ™1342 0.6 0.6 tetrasodium EDTA 0.5 0.5 perfume oil 0.5 0.5 sodiumchloride 0.3 0.3 sodium hydroxide 25% 0.92 0.9 butylated hydroxytoluene0.1 0.1 quaternium-15 0.05 0.05 colorants 0.001 0.001 deionized water qsad 100 100

Example 2 Shampoo Formulations for Oily Hair (with Conditioner)

Ingredients (a) (b) (c) sodium laureth sulfate 33.33 33.33 33.33 sodiumcocoyl sarcosinate 11 11 11 cocamide MEA 4 4 4 ketoconazole USP 0.5 0.751.2 Phospholipid PTC 0.5 0.25 0.8 glycol distearate 1.25 1.25 1.25polyquaternium-7 0.6 0.6 0.6 Carbopol ™ 1342 0.75 0.75 0.75 tetrasodiumEDTA 0.5 0.5 0.5 perfume oil 0.5 0.5 0.5 sodium chloride 0.3 0.3 0.3sodium hydroxide 25% 1.18 1.243 1.18 butylated hydroxytoluene 0.1 0.10.1 quaternium-15 0.05 0.05 0.05 colorants 0.0053 0.0053 0.0053deionized water qs ad 100 100 100

Example 3 Shampoo Formulations for Dry or Damaged Hair (withConditioner)

Ingredients (a) (b) (c) sodium laureth sulfate 30 30 30 sodium cocoylsarcosinate 10 10 10 cocamide MEA 4 4 4 ketoconazole USP 0.75 0.33 1Phospholipid PTC 0.25 0.67 1 glycol distearate 1.25 1.25 1.25polyquaternium-7 5 5 5 Carbopol ™ 1342 0.5 0.5 0.5 tetrasodium EDTA 0.50.5 0.5 perfume oil 0.5 0.5 0.5 sodium chloride 0.4 0.4 0.3 sodiumhydroxide 25% 0.7333 0.733 1.19 butylated hydroxytoluene 0.1 0.1 0.1quaternium-15 0.05 0.05 0.05 colorants 0.0018 0.0018 0.0018 deionizedwater qs ad 100 100 100

In all the formulations given above in Examples 1-3, the proportion ofsodium hydroxide may vary slightly, to arrive at the preferred pH levelof 6.9 to 7.4, and the proportion of salt (NaCl) may vary, to arrive atthe desired viscosity. Formulations prepared according to the improvedprocess and wherein the colorants have been omitted, have an off-whitepearlescent look.

Example 4 Combination of Phospholipid PTC and Ketoconazole (withConditioner)

Ingredients Percent purified water 44.30 sodium laureth sulfate 15.00sodium lauryl sulfate 10.00 TEA lauryl sulfate 12.00 Phospholipid PTC 2.10 ketoconazole  1.00 methylparaben  0.20 propylparaben  0.05cocamide MEA  5.00 ethylene glycol distearate  1.25 polyquaternium-7 3.00 imidazolidinyl urea  0.50 cocamidopropyl betaine  5.00 citric acid 0.35 fragrance  0.25 100.00 

Example 5 Combination of Phospholipid PTC and Elubiol (with Conditioner)

Ingredients Percent purified water 44.30 sodium laureth sulfate 15.00sodium lauryl sulfate 10.00 TEA lauryl sulfate 12.00 Phospholipid PTC 2.10 elubiol  1.00 methylparaben  0.20 propylparaben  0.05 cocamide MEA 5.00 ethylene glycol distearate  1.25 polyquaternium-7  3.00imidazolidinyl urea  0.50 cocamidopropyl betaine  5.00 citric acid  0.35fragrance  0.25 100.00 

In the formulations given above in Examples 4 and 5, the proportion ofcitric acid may vary slightly, to arrive at the preferred pH level of6.9 to 7.4. The formulations were prepared according to the improvedprocess and have an white-pearlescent look.

Example 6 Ketoconazole (2.1%) and Phospholipid PTC 2% and 1% (w/w)Shampoos (without Conditioner)

ketoconazole 2.100 g 2.100 g Phospholipid PTC 2.000 g 1.000 gimidazolidinyl urea 0.200 g 0.200 g disodium laureth sulfosuccinate15.000 g 15.000 g cocamide DEA 2.000 g 2.000 g hydrolized laurdimonium1.000 g 1.000 g macrogol 120 1.000 g 1.000 g perfume 0.200 g 0.200 ghydrocloric acid 0.400 g 0.400 g red erythrosine (FD & C No. 40) 0.002 g0.002 g sodium laureth sulfate 38.000 g 38.000 g sodium hydroxide 0.100g 0.100 g sodium chloride 0.500 g 0.500 g purified water q.s. ad 100 gq.s. ad 100 g

Example 7 In Vitro Synergisitic Inhibitory Effects between Ketoconazoleand Phospholipid PTC against Malassezia furfur

Checkerboard interaction experiments involving nine isolates ofMalassezia furfur (M. furfur) and the test substances with doublingdilution steps showed the combination of test substances to be highlysynergistic.

Ketoconazole was dissolved in DMSO to give a stock solution containing2000 μg/ml. Phospholipid PTC was diluted with ethanol to give a stocksolution containing 2000 μg/ml. A series of six further 3.162-folddilutions of each substances was prepared in the same solvent (Thisdilution factor=SQRT(10), so that every second dilution was therefore a10-fold dilution). Each of the seven concentrations of test substancewas then further diluted in water to 12 times the final testconcentration. An 8×8 checkerboard array of dilutions was next preparedin the wells of flat-bottomed, plastic microdilution plates with theketoconazole dilution series arranged vertically and the dilutions ofPhospholipid PTC arranged horizontally. Each well contained 10 μl ofsolution of each test substance. In an extra column of microdilutionwells, 10 μl volumes of matching aqueous dilutions of the solvents alonewere pipetted, to provide compound-free controls.

The panel of 9 M. furfur isolates used in the study was obtained fromthe fungal stock collection of the Department of Bacteriology andMycology at the Janssen Research Foundation. All of the isolates wereoriginally isolated from clinical material and three of them had beenfreshly isolated within 9 months prior to the study. The yeasts weremaintained by subculture on a modification of the medium called “H.Dixon's formulation” by Van Abbe, N. J. (1964) [The investigation ofdandruff. J. Soc. Cosmetic Chemists 15, 609-630]. This medium contained(per 1000 ml water): malt extract (Difco) 36 g; Mycological peptone(Oxoid) 6 g; Bacto-oxgall (Difco) 20 g; Tween 40 (Merck) 10 ml; glycerol(Difco) 2.5 ml; and Bacto-agar (Difco) 20 g. For use as a brothformulation the agar was omitted. Agar-based and broth versions of themedium were autoclaved for 5 min at 100° C.

Experimental inocula were prepared by incubation for 2 days at 30° C. inDixon broth maintained in constant rotation at 20 rpm in test tubesangled at 5° from the horizontal. The broth cultures were standardizedspectrophotometrically so they all gave an OD reading of 1.0 at 530 nm.These suspensions contained an average of 2×106 cells/ml as measured inagar plate counts. The yeasts were diluted 500-fold into Dixon broth togive suspensions containing 3-10×105 CFU/ml.

The inoculated medium was added in 100 μl volumes to the microdilutionwells already containing dilutions of the test substances. The plateswere sealed with adhesive stickers and incubated for 5 days at 30° C.The stickers were then removed and growth turbidity measured with theaid of a microplate reader as absorbance at 490 nm. For each combinationof test substances nine microplates were run in parallel, eachinoculated with a different M. furfur isolate. A tenth plate was set upinoculated with Dixon broth only, to provide negative control ODreadings.

With the aid of a computer spreadsheet template, the OD490 of eachmicroplate well containing combinations of test substances, correctedfor absorbance measured in the negative control plate, was expressed asa percentage of the mean OD490 of the eight test substance-free positivecontrol wells inoculated with M. furfur. The results were expressed inan 8×8 matrix and automatically shaded to indicate growth inhibition ator below 25% of control. In this way an indifferent interaction betweentwo test substances would appear as a dark rectangle at the bottom rightof the graphic, a synergistic interaction would appear as an inverted“L” shape at the bottom right of the graphic and an antagonisticinteraction would appear as an extension of the rectangle towards thetop left of the graphic. From the checkerboard results, minimalinhibitory concentrations (MIC) were determined as the lowestconcentrations of test compounds, alone and in combination with othercompounds, and fractional inhibitory concentrations (FIC) werecalculated for each compound by the formula:MIC(compound alone)/MIC(compound in presence of second compound)

The sum of the two FICs then gave a result of 1.0 for compounds with nointeractive effect (indifference), <1.0 for compounds with a synergisticinteraction and >1.0 for compounds with an antagonistic interaction.

Clearly positive results indicative of possible synergy were obtainedwith Phospholipid PTC. The sum of the fractional inhibitoryconcentrations (FIC) for the combination ketoconazole and PhospholipidPTC against 9 M. furfur isolates in vitro was:

M. furfur isolate no. FIC B 39387 0.63 B 45836 0.63 B 45838 0.63 B 580470.13 B 58200 0.63 B 58968 0.63 J95-0821 0.13 J95-0822 1 J95-1435 1

The degree of synergy extended well beyond one-dilution effects thatcould have arisen by chance. The activity of Phospholipid PTC incombination with ketoconazole was therefore further investigated againstthe test panel of nine isolates, but with smaller (two-fold) dilutionsteps in the concentration series. The sum of the fractional inhibitoryconcentrations (FIC) for the combination ketoconazole and PhospholipidPTC against 9 M. furfur isolates in vitro was:

M. furfur isolate no. FIC B 39387 0.38 B 45836 0.38 B 45838 0.16 B 580470.38 B 58200 0.19 B 58968 0.38 J95-0821 0.38 J95-0822 0.75 J95-1435 0.38

The results confirm unequivocally that both test compounds indeedinteract synergistically with ketoconazole against M. furfur in vitro.

1. A body or hair cleansing composition comprising: (a-1) one or moreantifungals inhibiting fungal ergosterol biosynthesis as a first activeingredient, (a-2) a synthetic amphotheric phospholipid as a secondactive ingredient, and (b) at least one surfactant other than aphospholipid,

Wherein R represents a straight, saturated, mono-unsaturated, orpoly-unsaturated C7-19 alkyl group; x represents 1, 2, or 3; and x+y=3;and mixtures thereof; and (b) at least one surfactant other than aphospholipid.
 2. A composition comprising (a-1) one or more antifungalsinhibiting fungal ergosterol biosynthesis as a first active Ingredient,wherein the antifungal inhibiting fungal ergosterol biosynthesis is anazole selected from the group comprising ketoconazole, econazole,elubiol, miconazole, itraconazole, fluconazole, or a mixture is thereof,or is an allylamine selected from the group comprising terbinafine,naftifine, or a mixture thereof, (a-2) a synthetic amphotericphospholipid as a second active antifungal ingredient, wherein thephospholipid has the formula

Wherein R represents a straight, saturated, mono-unsaturated, orpoly-unsaturated C7-19 alkyl group; x represents 1, 2 or 3; and x+y=3;and mixtures thereof, and (b) a carrier.
 3. A composition according toclaim 1, wherein the first and the second active ingredients are presentin quantities producing a mutual synergistic effect on the inhibition ofthe growth of Malassezia furfur.
 4. A composition according to claim 1,wherein the first active ingredient is present in an amount ranging fromabout 0.1% to about 2% (w/w) and the second active ingredient is presentin an amount ranging from about 0.04% to about 10% (w/w), the amount ofthe latter being expressed as weight of phospholipid.
 5. A compositioncomprising (a-1) one or more antifungals inhibiting fungal ergosterolbiosynthesis as a first active ingredient, (a-2) a amphotericphospholipid as a second antifungal active ingredient, wherein thephospholipid has the formula

Wherein R represents a straight, saturated, mono-unsaturated, orpoly-unsaturated C7-19 alkyl group; x represents 1, 2, or 3; and x+y=3 ;and mixtures thereof; and (b) at least one surfactant, wherein saidcomposition is formulated as shampoo.
 6. A shampoo according to claim 5further comprising one or more of a foaming agent, a thickenersufficient to give the final formulation a viscosity in the range of4,000 to 9,000 mPa·s at room temperature, a preservative, ananti-oxidant, and acid or base or buffer sufficient to give the shampooa pH in the range of from about 4 to about
 10. 7. A shampoo according toclaim 6 wherein the surfactant is selected from the group consisting ofsodium C14-16 olefin sulfonates, sodium lauryl sulfate, sodium laurethsulfate, cocamidopropylamine oxide, lauryl amine oxide, lauramidodi-ethanol amide, cocamidopropyl betaine, lauryl dimethyl betaine,cocodimethyl sulphopropyl betaine, sodium cocoyl sarcosinate, disodiumoleamido mono-isopropanol amide sulfosuccinate, disodium cocamidomono-isopropanol amide sulfosuccinate, disodium laureth sulfosuccinate,cocoamphocarboxylglycinate, disodium oleamido mono-ethanol amidesulfosuccinate, amine glycinates, amine propionates and amine sultanes,and mixtures thereof.
 8. A shampoo according to claim 6 wherein thefoaming agent is a fatty acid mono- and di-alkanolamide selected fromthe group consisting of cocamide mono-ethanol amide, cocamide di-ethanolamide, oleamide mono-ethanol amide, oleamide di-ethanol amide, andmixtures thereof.
 9. A shampoo according to claim 6 wherein theantioxidant is butylated hydroxytoluene or butylated hydroxyanisoleemployed in an amount of about 0.01 to about 1% (w/w).
 10. A shampooaccording to claim 6 further comprising a conditioner.
 11. A shampooaccording to claim 6 further comprising one or more pearlizing agentsselected form the group consisting of ethylene glycol distearate,ethylene glycol monostearate and mixtures thereof.
 12. A shampooaccording to claim 6 further comprising one or more fragrances and oneor more colorants.
 13. A process for preparing a shampoo formulation asdefined in claim 6 comprising the steps of: (a) heating a solution ofthickener and deionized water, (b) mixing the surfactants, the foamingagent and optionally the pearlizing agent with the solution of (a), (c)mixing the BHT with the solution of (b), (d) mixing the antifungal withthe solution of (c), (e) dispersing the phospholipid in the mixture of(d), (f) allowing the suspension of (e) to cool somewhat and mixingtherewith the preservative(s), the sodium chloride for thickening to therequired viscosity, and optionally the conditioner, the fragrance(s) andcolorat(s), (g) adding acid, base or buffer to the solution of (f) toyield a pH in the range of 4 to 10, and (h) adding deionized water tothe solution of (g) to 100%.
 14. The composition according to claim 5wherein the antifungal inhibiting fungal ergosterol biosynthesis is anazole selected from the group consisting of ketoconazole, econazole,elubiol, miconazole, itraconazole, fluconazole, and a mixture thereof,or is an allylamine selected from the group consisting of terbinafine,naftifine, and a mixture thereof.
 15. The composition according to claim5 wherein the first and the second active ingredients are present inquantities producing a mutual synergistic effect on the inhibition ofthe growth of Malassezia furfur.
 16. The composition of claim 5 whereinthe first active ingredient is present in an amount ranging from about0.1 % to about 2% (w/w) and the second active ingredient is present inan amount ranging from about 0.04% to about 10% (w/w), the amount of thelatter being expressed as weight of phospholipid.
 17. The composition ofclaim 1 wherein the first active ingredient is ketoconazole and thesecond active ingredient is cocamidopropylphosphatidyl PG-dimoniumchloride, and wherein the first and the second active ingredients arepresent in quantities producing a mutual synergistic effect on theinhibition of the growth of Malassezia furfur.
 18. A compositionaccording to claim 2 formulated as a shampoo.
 19. The compositionaccording to claim 2 wherein the first and the second active ingredientsare present in quantities producing a mutual synergistic effect on theinhibition of the growth of Malassezia furfur.
 20. The composition ofclaim 2 wherein the first active ingredient is present in an amountranging from about 0.1% to about 2% (w/w) and the second activeingredient is present in an amount ranging from about 0.04% to about 10%(w/w), the amount of the latter being expressed as weight ofphospholipid.
 21. The composition of claim 2 wherein the first activeingredient is ketoconazole, and the second active ingredient iscocamidopropylphosphatidyl PG-dimonium choloride, and wherein the firstand the second active ingredients are present in quantities producing amutual synergistic effect on the inhibition of the growth of Malasseziafurfur.